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1
* Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555;
Shriners Burns Hospital, Galveston, TX 77550; and
University of California-Davis Medical Center, Sacramento, CA 95817
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1) in cultures, while 2355–6900
pg/ml MIP-1 were produced by healthy donor PBMC, stimulation with
anti-human CD3 mAb. Healthy chimeras (SCID mice inoculated with
healthy donor PBMC) treated with anti-human MIP-1 mAb and
patient chimeras (SCID mice reconstituted with burned patient PBMC)
were susceptible (0% survival) to infectious complications induced by
well-controlled cecal ligation and puncture. In contrast, patient
chimeras treated with human recombinant MIP-1 and healthy chimeras
were resistant (
77–81% survival). Similarly, after anti-mouse
CD3 mAb stimulation, splenic mononuclear cells from burned mice (6 h to
3 days after thermal injury) did not produce significant amounts of
MIP-1 in their culture fluids. Normal mice treated with
anti-murine MIP-1 mAb and burned mice were susceptible to cecal
ligation- and puncture-induced infectious complications, while burned
mice treated with murine recombinant MIP-1 and normal mice were
resistant. Burned patients seemed to be more susceptible to infectious
complications when the production of MIP-1 was
impaired. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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More recently, the cascade of events leading from local infection or initial injuries to systemic inflammatory response syndrome (SIRS),3 sepsis, multiple organ failure, and death has been described in patients with severe burn injuries (11). The mediators of compensatory anti-inflammatory response syndrome (CARS), such as IL-4, IL-10, and IL-13, regulate the inflammatory responses in SIRS (11). However, excessive compensatory anti-inflammatory reactions developed in these patients commonly induce severe immunosuppression (11). Therefore, local infections at injury sites will be easily spread into whole-body infections in burned patients with SIRS or CARS.
In recent experiments PBMC from patients with severe thermal injuries
were unable to produce macrophage inflammatory protein 1 (MIP-1).
Recently, MIP-1, a member of the 
-chemokine subfamily, has been
described as a modulator of host defense against infection
(12, 13, 14, 15). The absence of MIP-1 greatly impairs the
recruitment of monocytes and neutrophils into infected organs
(12, 13, 14, 15). In addition, MIP-1 is able to induce
activated macrophages that kill Escherichia coli,
Trypanosoma cruzi, or Klebsiella pneumoniae
(16, 17, 18) and to be required for the clearance of
Cryptococcus neoformans or Listeria monocytogenes
in vivo (16, 17). In addition, CCR1 (a receptor for
MIP-1) knockout mice have an increased susceptibility to infection
with Aspergillus fumigatus (19). Furthermore,
MIP-1 augments CTL- and NK-mediated cytolysis (15).
These facts have led to the question of whether the impaired ability to
produce MIP-1 is associated with the increased susceptibility of
burned patients to infection. Therefore, the present study investigates
the resistance of burned patient-SCID mouse chimeras, supplemented with
or depleted of MIP-1, to infectious complications induced by cecal
ligation and puncture (CLP). Further, the contribution of MIP-1 to
the host’s protective immunity against CLP-induced sepsis was studied
in a mouse model of thermal injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty-five children (27 male and 18 female; mean age, 7.3 years)
with burn injuries of >40% of their total body surface area (five
scald burns, two electrical burns, two flash burns, and 36 flame
burns), who were admitted to the Shriners Burns Hospital for Children
(Galveston, TX) from April 2000 to March 2001, were enrolled in the
study. The institutional review board for human investigation at
University of Texas Medical Branch (Galveston, TX) approved all human
experiments in the study. The patients were taken to the operating room
within 24 h of their admission to Shriners Burns Hospital for
Children, where complete excision of the burn was undertaken with
autografting or allografting as clinically indicated. The
administration of antibiotics was continued until the dressings were
removed on postoperative day 4. Blood specimens were obtained from
patients within 3 wk of burn injuries, as listed in Table I
.
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Seven- to 8-wk-old pathogen-free male BALB/c mice and SCID mice (BALB/c origin) purchased from The Jackson Laboratory (Bar Harbor, ME) were used in this study. The animal care and use committee of University of Texas Medical Branch approved all procedures using animals.
Reagents, media, and cells
Human recombinant MIP-1 (rMIP-1) and murine
rMIP-1 were obtained from PeproTech (Rocky Hill, NJ). mAbs for human
MIP-1 and murine MIP-1 were obtained from R&D Systems
(Minneapolis, MN). Anti-human CD3 mAb was purchased from Ancell
(Bayport, MN). Anti-mouse CD3 mAb was obtained from BD PharMingen (San
Diego, CA). PBMC were isolated from heparinized whole blood of both
healthy donors and thermally injured patients by Ficoll-Hypaque density
gradient centrifugation (9). T cells were prepared from spleens of mice
by T cell enrichment columns (R&D Systems) (20). The
purity of these cells was >96%, as described in previous studies
(20). PBMC and murine splenic T cells were cultured with RPMI 1640
medium supplemented with 10% FBS, 2 mM L-glutamine,
antibiotics, 30 mM HEPES, and 5 x 10-5
M 2-ME.
Human mouse chimeras
SCID mice were reconstituted with PBMC (8 x 106 cells/mouse i.v.) from thermally injured patients and designated patient chimeras. SCID mice inoculated with the same amount of PBMC from healthy donors were designated healthy chimeras and used as a control. Immediately after PBMC inoculation, these chimeras were exposed to CLP. Significant numbers of human cells are recovered from lungs, livers, and spleens of these chimeras 1 day to 2 mo after the inoculation. SCID mice do not have functioning T and B cells. Therefore, SCID mice inoculated with PBMC from healthy donors or thermally injured patients express immune responses representative of the PBMC donors.
A mouse model of thermal injury
A third degree flame burn on 15% of the total body surface
area was produced in mice according to our previously reported protocol
(21). Mice were anesthetized with pentobarbital (40 mg/kg)
administered i.p. Electric clippers were used to shave the hair on the
back of each mouse from groin to axilla. Thermal injury was produced by
pressing a custom-made insulated mold (with a 2.5- x 3.5-cm window)
firmly against the shaved back of each mouse and subsequently exposing
the area to a gas flame for 9 s. A Bunsen burner equipped with a
flame-dispersing cap produced the gas flame. The result was a third
degree burn on 15% of the total body surface area for a 26-g mouse.
Immediately after thermal injury, physiologic saline (4 ml/mouse i.p.)
was administered for fluid resuscitation. Animals were then housed
until used for experiments. Control mice, not exposed to the gas flame,
had their back hair shaved and received physiologic saline (4 ml/mouse
i.p.).
Infectious complications
A well-controlled CLP technique was used in this study because infectious complications induced by CLP have been described as similar to sepsis developed in various patients (22, 23, 24). This laboratory developed a modified procedure to perform a well-controlled cecal ligation and 26-gauge puncture (25). To perform CLP, mice were anesthetized with pentobarbital (50 mg/kg i.p.). To ensure the consistent severity of CLP, a minimum sized incision (<1.0 cm) to the lower right quadrant of the abdomen was made, and the cecum was drawn out. To avoid dehydration, the exposure of the cecum to air was kept to a minimum. The distal one-third was ligated with silk suture, and two punctures were made on the ligated cecum with a 26-gauge needle. Then, the cecum was returned and placed away from the incision. The peritoneal incision was closed using sutures (not surgical glue). All mice were treated with 2 ml sterile saline (s.c.) for fluid resuscitation during the postoperative period. From our accumulated data, our CLP induced by a 26-gauge needle resulted in a 7.7% lethality rate (5 of 65) in normal mice. We observed these mice daily for 7 days after CLP.
In some experiments patient chimeras were treated with 250 ng/mouse of
human rMIP-1 (s.c.) 12 h before as well as 12 and 24 h
after CLP. Also, healthy chimeras were treated with 10 µg/mouse of
anti-human MIP-1 mAb (s.c.) 12 h before and immediately
after CLP. In a mouse model of thermal injury, burned mice were treated
with 200 ng/mouse of murine rMIP-1 (s.c.) 12 h before as well
as 12, 24, and 48 h after CLP. As controls, burned mice and normal
mice were treated with saline or murine rMIP-1 at the same dose and
schedule, respectively. In addition, normal mice were treated with 10
µg/mouse of anti-murine MIP-1 mAb (s.c.) 2 h before and
immediately after CLP. As controls, burned mice and normal mice were
treated with anti-murine MIP-1 mAb or control Ig at the same
dose and schedule, respectively. The doses and schedules of
administration for human and murine rMIP-1 and mAbs were determined
during preliminary studies. All these mice were observed daily to
determine their mortalities (percent survival, 7 days after CLP). The
percent survival of tested groups was compared with that of appropriate
controls. All experiments were performed two or three times, and the
results presented show data from repeated experiments.
Production and assay of MIP-1
To produce MIP-1 in vitro, 2 x
106 cells/ml PBMC from healthy donors or
thermally injured patients were suspended in RPMI 1640 medium
supplemented with 10% FBS, 2 mM L-glutamine, antibiotics,
30 mM HEPES, and 5 x 10-5 2-ME (complete
medium), then stimulated with anti-human CD3 mAb (Ancell; 2.5
µg/ml) for 48 h at 37°C. In some experiments 2 x
106 cells/ml splenic T cells from normal mice or
mice on various days after thermal injury were cultured in complete
medium and stimulated with anti-mouse CD3 mAb (BD PharMingen; 2.5
µg/ml) for 24–72 h. Culture fluids harvested by centrifugation were
assayed for MIP-1 using ELISA according to the manufacturer’s
protocols. To determine the amounts of circulating MIP-1 in human
mouse chimeras, specimens obtained from healthy and patient chimeras 1
day after stimulation with anti-human CD3 mAb (10 µg/mouse i.v.)
were assayed by ELISA. The detection limit for cytokines in our assay
system was 18 pg/ml. Each assay was performed three times.
Statistical analysis
The results obtained were analyzed statistically by ANOVA. Survival curves were analyzed using the Kaplan-Meier test. All calculations were performed using the software StatView 4.5 from Brain Power (Calabasas, CA). The result was considered significant if p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by PBMC from thermally injured patients
To induce the production of MIP-1, PBMC isolated from blood
specimens taken from thermally injured patients was stimulated with
anti-human CD3 mAb. PBMC from five healthy children (healthy PBMC)
were used as a control. While healthy PBMC (2 x
106 cells/ml) produced 2355–6900 pg/ml MIP-1
in culture supernatants 48 h after the anti-human CD3 mAb
stimulation, the production of MIP-1 was not detected (<18 pg/ml)
in PBMC cultures from 41 (91%) of 45 burned patients (Table I
). In
PBMC cultures of the four remaining patients, the amount of MIP-1
produced (average, 332 pg/ml) was significantly decreased compared with
that of healthy PBMC (average, 3937 pg/ml; p <
0.0001).
MIP-1 in sera of human mouse chimeras
SCID mice were reconstituted with 8 x
106 cells/mouse of patient PBMC shown to be
unable to produce MIP-1 (patient chimeras) or the same number of
PBMC from healthy donors (healthy chimeras). To induce MIP-1
production in vivo, healthy chimeras and patient chimeras were
stimulated i.v. with anti-human CD3 mAb, and serum specimens were
harvested from these chimeras 1 day after mAb stimulation. When healthy
chimeras were stimulated with anti-human CD3 mAb, 743–980 pg/ml
human MIP-1 was detected in sera. No human MIP-1 was detected in
sera of patient chimeras (Fig. 1).
Neither human MIP-1 nor murine MIP-1 was found in sera of
chimeras without any stimulation.
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The importance of MIP-1 to the resistance of healthy and
patient chimeras to CLP-induced infectious complications was examined.
The results obtained are shown in Fig. 2.
All (n = 12) healthy chimeras treated with
anti-human MIP-1 mAb died within 3 days of CLP, while 23% (6 of
26) of healthy chimeras treated with control Ig died (Fig. 2A; p < 0.05). In addition, all
(n = 16) patient chimeras treated with saline died
within 4 days of CLP, while 19% (3 of 16) of patient chimeras treated
with human rMIP-1 died (Fig. 2B; p <
0.001).
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in cultures of splenic T cells from
burned mice
The results obtained in the chimera experiments were further
studied in a mouse model of thermal injury. In response to the
anti-mouse CD3 mAb stimulation, splenic T cells from normal mice
produced 5.8 ng/ml MIP-1 in their culture fluids 72 h after
cultivation (Fig. 3). However, under the
same conditions, splenic T cells from mice produced 0.2 ng/ml MIP-1
18 h after thermal injury (Fig. 3). Cultures of splenic T cells
from mice first demonstrated impaired MIP-1 production 6 h
after thermal injury (Fig. 4). The
maximum suppression of MIP-1 production was shown when splenic T
cells from mice 18 h after thermal injury were stimulated in vitro
with anti-mouse CD3 mAb (Fig. 4). About 50% suppression of
MIP-1 production (2.9 ng/ml) was observed when splenic T cells from
mice 9 days after burn injury were stimulated with anti-mouse CD3
mAb. MIP-1 production in the mice was not recovered until 3 wk
following thermal injury.
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to the resistance of normal and burned mice
against CLP-induced sepsis
In the next experiments the importance of MIP-1 to the
resistance of mice against CLP was examined. While 20% (2 of 10) of
normal mice, treated with control Ig died after CLP, an 88% (seven of
eight) mortality rate was produced when mice treated with
anti-MIP-1 mAb were subjected to the same procedure (Fig. 5; p < 0.001). In
addition, groups of burned mice undergoing CLP (CLP-burned mice) were
treated with saline (control) or murine rMIP-1. Mortality in
CLP-burned mice treated with murine rMIP-1 was 22% (2 of 9), while
91% (10 of 11) of burned mice treated with saline died within 4 days
of CLP (Fig. 6; p <
0.001). In preliminary studies MIP-1 was administered to mice on
three different administration schedules. These include 1) 2 and
12 h before CLP, prophylactically, two times in total; 2) 2 h
before, 12 and 24 h after CLP, prophylactically and
therapeutically, three times in total; and 3) 2 and 12 h after
CLP, therapeutically, two times in total. Protective effects of
MIP-1 were demonstrated in all three groups. The percentages of
survival of CLP mice treated with MIP-1 were as follows:
prophylactic treatment, 71% (10 of 14 mice); therapeutic treatment,
57% (8 of 14 mice); and prophylactic and therapeutic treatment, 83%
(15 of 18 mice). This indicated that the infectious complications of
CLP could be controlled by the therapeutic and/or prophylactic
administration of MIP-1. The results observed in human mouse
chimeras and burned mice indicate that the susceptibility of burned
patients to infectious complications is increased when MIP-1
production is impaired.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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responsiveness in
cultures of PBMC from patients with severe thermal injuries was
demonstrated. After stimulation with anti-CD3 mAb, PBMC from five
healthy donors (healthy PBMC) produced 2355–6900 pg/ml MIP-1 in
their culture fluids. However, PBMC from 41 of 45 severely burned
patients (91%) failed to produce MIP-1 in cultures following
stimulation with anti-human CD3 mAb. Changes in the numbers of
lymphoid progenitor cells from burned patients have not been reported.
Although the decrease in numbers of granulocyte stem cells has been
reported in burned patients (26), we have no information
for the precursor of MIP-1-producing cells influenced by thermal
injury. We think, however, that the impaired MIP-1 production in
thermally injured patients may not be correlated to the absence of
possible precursor cell populations. The total number of PBL in healthy
donors was not significantly changed after thermal injuries. To
date, we have no information on the difference of MIP-1-producing
cell numbers in patient PBL and healthy PBL. Further studies are
required.
Both healthy chimeras (SCID mice inoculated with healthy donor PBMC)
treated with anti-human MIP-1 mAb and patient chimeras (SCID
mice reconstituted with burned patient PBMC) were susceptible (0%
survival) to infectious complications induced by CLP, while patient
chimeras treated with human rMIP-1 and healthy chimeras were
resistant (77–81% survival). Similarly, after the anti-mouse CD3
mAb stimulation, splenic mononuclear cells from mice 6 h to 3 days
after thermal injury did not produce significant amounts of MIP-1 in
their culture fluids. The production of MIP-1 in mice was not
recovered until 3 wk after thermal injury. Both normal mice treated
with anti-murine MIP-1 mAb and burned mice were susceptible to
CLP-induced infectious complications, while burned mice treated with
murine rMIP-1 and normal mice were resistant. All these results
indicate that the susceptibility of burned patients to infectious
complications is increased when the production of MIP-1 is impaired.
Recently, we published experimental results on the capability of
MIP-1 to activate macrophages. Phagocytic and killing activities of
peritoneal macrophages against Pseudomonas aeruginosa were
increased by MIP-1 in vitro and in vivo (25, 27).
Further, after the inoculation of macrophages activated by MIP-1
(peritoneal macrophages from normal mice treated with MIP-1), 79%
of SCID-M mice (SCID mice depleted with macrophage function) subjected
to CLP survived, while 44% of SCID-M mice inoculated with freshly
isolated peritoneal macrophages and 0–11% of SCID-M mice treated with
saline survived after CLP. These results suggest that CLP-induced
infectious complications are influenced by macrophages activated with
MIP-1.
It is well documented that a level of serum norepinephrine (NE)
increased in patients just after thermal injury (28, 29, 30).
In a model of thermal injury the increased NE level was constantly
demonstrated in the sera of mice 1–12 h after burn injury
(31). In preliminary studies MIP-1 production in
cultures of normal splenic T cells stimulated with anti-mouse CD3
mAb was shown to be markedly inhibited by 10-8 M
NE. MIP-1 production in splenic T cells treated with NE returned to
a normal level when the cells were also treated with
10-5 M propranolol, an NE antagonist. In
addition, MIP-1 production was not impaired in cultures of splenic T
cells from burned mice injected with 6-hydroxydopamine, an inhibitor of
sympathetic nerve termini. These results suggest that NE production by
stimulation with injury has an important role in impairing MIP-1
production. In recent studies (32) monocyte
chemoattractant protein 1 (MCP-1) was found in sera of mice early after
thermal injuries (2–24 h after burn injury). Without any stimulation,
splenic macrophages from mice produced MCP-1 in their culture fluids
early after burn injury (32). IL-4 was produced by splenic
T cells cultured with MCP-1- or MCP-1-producing macrophages in
dual-chamber transwells. Since IL-4 has the ability to inhibit MIP-1
gene expression on human monocytes and alveolar macrophages
(33), these facts suggest that through the production of
IL-4, MCP-1 produced by stimulation with burn injuries may have the
ability to inhibit MIP-1 production. In addition, corticosteroids
and PGE2 have the ability to impair MIP-1
production, because these substances have an ability to generate
IL-4-producing cells (Th2 cells) (34, 35). These results
suggest that substances (neuropeptides, stress hormones,
PGE2, and MCP-1 among others) released from hosts
early after thermal injury may play a role as inhibitors of MIP-1
production in thermally injured patients.
Studies show that mast cells and TNF- released from mast cells
initiate the cascade of host defense against CLP-induced sepsis
(36). Therefore, the increased susceptibility of mast cell
knockout mice to infectious complications has been demonstrated
(36). Recently, MIP-1 has been reported
(37) to be implicated in the degranulation and recruitment
of mast cells. Through the induction of TNF- from mast cells,
MIP-1 has a capability to activate neutrophils and macrophages
(37), suggesting that MIP-1 may play a role in mast
cell-associated host resistance against sepsis. On the other hand,
multiple organ failure, a major reason for the high mortality rates of
patients with sepsis, has been observed when sepsis-associated
lymphocyte apoptosis was developed throughout the body
(38). The administration of caspase inhibitors to animals
with CLP-induced sepsis has been shown to prolong the life span of
these animals (39). Recently, a mixture of -chemokines
(MIP-1, MIP-1, and RANTES) has been reported to inhibit apoptosis
induced by pokeweed mitogen or staphylococcal enterotoxin B in cultures
of T cells from AIDS patient (40). In addition,
anti-CD3-triggered apoptotic death of T cells has been inhibited by
the same mixture of -chemokines (40). The fact that
MIP-1 inhibits the apoptotic death of lymphocytes suggests that
MIP-1 may have the ability to regulate the multiple organ failure.
Further, MIP-1 was shown to be required for macrophages to produce
IL-12 (41). IL-12 is key in promoting the differentiation
of naive T cells into Th1 cells, and it functions as a costimulus for
maximal IFN-
production by already differentiated Th1 cells
(42, 43, 44). In fact, a representative Th1 cytokine (IFN-)
was not induced by the anti-human CD3 mAb stimulation in cultures
of burned patient PBMC without an ability to produce IL-12
(45). Th1 cytokines are needed to convert macrophage
functions from resting to bactriocidal (46). In addition,
IL-12 has been shown to inhibit T cell death by the regulation of
caspase processing (47). All these findings suggest that
MIP-1 plays a key role in improving host resistance against sepsis.
The results reported herein indicate that the impairment of innate
immunity in hosts exposed to severe thermal injuries is associated with
the decreased production of MIP-1.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fujio Suzuki, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0435. E-mail address: fsuzuki{at}utmb.edu
3 Abbreviations used in this paper: SIRS, systemic inflammatory response syndrome; CARS, compensatory anti-inflammatory response syndrome; CLP, cecal ligation and puncture; MCP-1, monocyte chemoattractant protein 1; MIP-1, macrophage inflammatory protein 1; NE, norepinephrine; rMIP-1, recombinant MIP-1.
Received for publication January 30, 2002. Accepted for publication August 13, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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for an inflammatory response to viral infection. Science 269:1583. is a critical mediator of host defense against invasive pulmonary aspergillosis in neutropenic hosts. J. Immunol. 165:962. (MIP-1) is required for the effector phase of pulmonary cell-mediated immunity to a Cryptococcus neoformans infection. J. Immunol. 159:318.[Abstract]
in vivo. J. Immunol. 162:5423., and MIP-1 induce trypanocidal activity in human macrophages via nitric oxide. Infect. Immun. 66:4690. (MIP-1) display anti-bacterial activities in vitro and in vivo. FASEB J. 15:A651.
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(MIP-1) induces the IL-12 production and improves the polarization of Th1 responses in thermally injured mice. J. Allergy Clin. Immunol. 107:S81.
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; 10 µg/mouse
s.c.) or anti-human MIP-1
; 10 µg/mouse s.c.) or anti-murine MIP-1
; 10 µg/mouse s.c.) after the same CLP.